S248: SIERRA TRIAL RESULTS WITH A TARGETED RADIOTHERAPY, IOMAB-B, A MYELOABLATIVE CONDITIONING WITH REDUCED INTENSITY TOLERABILITY YIELDS HIGH CR, LONG TERM SURVIVAL IN HSCT INELIGIBLE ACTIVE R/R AML
Authors: Boglarka Gyurkocza, Stuart Seropian, Hannah Choe, Mark Litzow, Camille Abboud, Nebu Koshy, Patrick Stiff, Benjamin Tomlinson, Sunil Abhyankar, James M Foran, Parameswaran Hari, George Chen, Zaid Al-Kadhimi, Partow Kebriaei, Mitchell Sabloff, Johnnie Orozco, Katarzyna Jamieson, Margarida Silverman, Koen Van Besien, Michael Schuster, Arjun Law, Sameem Abedin, Karilyn Larkin, Scott Rowley, Pashna Munshi, Rachel Cook, Sebastian Mayer, Moshe Yair Levy, Hillard Lazarus, Brenda Sandmaier, Vijay Reddy, Jennifer Spross, Kathleen Mcnamara, Elaina Haeuber, Madhuri Vusirikala, Akash Nahar, John Pagel, Sergio Giralt, Avinash Desai, Rajneesh Nath
Journal: HemaSphere (2023)

Background: Despite recent advances in the treatment of acute myeloid leukemia (AML), prognosis for patients with relapsed, refractory (R/R) disease remains poor. The only potentially curative option for these patients is allogeneic hematopoietic stem cell transplantation (HSCT). However, only a minority reach complete remission (CR) or sufficient disease control to allow for HSCT, and moreover induction and conditioning regimens are poorly tolerated in the older population. Iomab-B (131I-apamistamab) is an anti-CD45 radioimmunoconjugate delivering targeted myeloablative radioactivity to stem cells and leukemic blasts with reduced intensity tolerability. Aims: SIERRA (NCT02665065) is a multi-centre, randomized, controlled phase 3 study comparing the efficacy of Iomab-B based conditioning versus physician's choice of conventional care (CC) in older, R/R AML with active disease routinely ineligible for HSCT. Primary endpoint was durable CR (dCR), defined as CR ≥6 mos with or without platelet recovery (CRp). Methods: Pts ≥55 years of age with active R/R AML were randomized (1:1) to CC or Iomab-B with fludarabine and total body irradiation (2 Gy) followed by HSCT. CC pts achieving CR received physician's choice conditioning and HSCT. Pts not achieving CR could crossover (CO) to Iomab-B-based conditioning followed by HSCT. Assessment for CR/CRp occurred between days 28-56 post HSCT or initiation of therapy on the CC arm. Pts in CR/CRp were evaluated for the primary endpoint of dCR 6 mos after achieving initial CR/CRp. Results: Baseline pt characteristics were balanced between both arms. 61% pts failed targeted therapies prior to enrolment, of whom 66% received venetoclax-based therapy. Median time to HSCT was 29 and 66.5 days on Iomab-B and CC arms (CC pts who had CR/CRp), respectively. The median infused activity of Iomab-B was 664.4 and 613.3 mCi in Iomab-B and CO arms respectively with median dose to marrow of 16 Gy in both arms. All pts who received the therapeutic dose of Iomab-B (n=66) underwent HSCT vs 14 (18.2%) on CC arm. Of evaluable pts (Iomab: 59; CC: 64), 44 (74.6%) pts on the Iomab-B arm achieved initial CR/CRp compared to 4 (6.3%) on CC. Durable CR rates were 22% vs 0% (95% CI; 12.29, 34.73; p<0.0001). The median overall survival (OS) was 6.4 vs 3.2 mos for pts receiving Iomab-B-based conditioning followed by HSCT vs non-CO pts on CC arm, respectively. Median OS in the CO vs non-CO cohorts on the CC arm was 7.1 vs 3.2 mos (HR=0.51; 95% CI [0.31, 0.85]; p=0.0078). OS in pts receiving Iomab-B and HSCT achieving dCR (n=13) was 92% and 60% at 1 and 2 yrs respectively (Figure 1). Event-free survival (EFS) at 6 mos on Iomab-B vs CC was 26% vs 0.2% (HR=0.22; 95% CI [0.15, 0.34]; p<0.0001). Iomab-B-based conditioning followed by HSCT was well tolerated with a favourable safety profile, with lower rates of sepsis in pts receiving Iomab-B based conditioning vs pts undergoing standard of care HSCT.Summary/Conclusion: In pts ≥55 yrs with active R/R AML, Iomab-B was able to safely deliver myeloablative doses of targeted radiation to bone marrow. Iomab-B based conditioning with HSCT resulted in rapid engraftment and high initial CR/CRp rates, a favourable toxicity profile and resulted in statistically significant improvement in the pre-specified primary endpoint of dCR. The majority of pts who achieved dCR are long term survivors, in whom OS and EFS was significant. Iomab-B based conditioning was well-tolerated and provided access to HSCT with curative potential in a vulnerable pt population traditionally not considered eligible for HSCT. Keywords: Radioimmunotherapy, Acute myeloid leukemia, Conditioning, Allogeneic hematopoietic stem cell transplant